Multi-tissue multi-omics integration reveals tissue-specific pathways, gene networks and drug candidates for type 1...

Although genome-wide association studies (GWAS) have identified loci associated with type 1 diabetes, the specific pathways and regulatory networks linking these loci to disease pathology remain largely unknown. We hypothesised that type 1 diabetes genetic risk factors disrupt tissue-specific biological pathways and gene networks that ultimately lead to beta cell loss.

We conducted a multi-tissue multi-omics analysis that integrates human GWAS data for type 1 diabetes with tissue-specific regulatory data for gene expression and gene network models across relevant tissues to highlight key pathways and key driver (KD) genes contributing to type 1 diabetes pathogenesis. KD genes were validated using islet-specific gene expression and protein data from non-obese diabetic (NOD) mice compared with type 2 diabetic and non-diabetic mouse models. Drug repositioning predictions were generated using the INCS L1000 and PharmOmics platforms, and candidate drugs were tested using electronic medical records (EMRs) of individuals with type 1 diabetes from the OneFlorida+ Clinical Data Network.

Our integrative genomics approach identified known immune pathways across multiple tissues, such as adaptive immune responses, cytokine-mediated inflammation, primary immunodeficiency, and interactions between lymphoid and non-lymphoid cells. Tissue-specific signals included genes related to type 2 diabetes in lymphocytes, viral response pathways in macrophages and monocytes, and Notch signalling in adipose tissue and immune cells. In pancreatic islet analysis, we observed significant enrichment for type 1 diabetes and type 2 diabetes gene sets alongside immune-related pathways, including antigen processing, systemic lupus erythematosus and IFN signalling. Removing HLA genes from the analysis revealed additional immune pathways, such as retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated protein 5 (MDA5) induction of interferons, together with melanogenesis, steroid hormone synthesis and iron transport. Network modelling highlighted the autoimmune basis of disease, with KDs such as FYN, TAP1, WAS and HLA-B/C/G, as well as additional immunomodulatory proteins such as LCK, LCP2 and genes such as EMR1 and GC. These KDs were further supported by gene and protein expression data from NOD mice. We additionally highlight various drug classes that target the type 1 diabetes genetic networks and may be useful to delay type 1 diabetes development; some of these were supported by our EMR screen.

Our multi-tissue multi-omics approach provides a detailed landscape of the tissue-specific genetic networks and regulators underlying type 1 diabetes. This analysis confirms the roles of known immune pathways while uncovering additional regulatory elements and disease-associated networks, thus expanding our understanding of type 1 diabetes pathogenesis. The identification of potential drug candidates through network analysis, with supporting evidence from EMRs, offers potential therapeutic strategies for targeting disease pathways and holds promise for delaying or preventing type 1 diabetes progression.